Project Summary: Medulloblastoma is a malignant brain tumor in children with significant mortality and poor outcomes secondary to toxicity of cun-ent therapy. Evidence points to medulloblastoma originating from neural precursor cells located within the cerebelluni and roles for Sonic hedgehog and Wnt signaling pathways in this brain tumor have also been implicated. The long-term goals ofthis project are to better understand the developmental origins and molecular signatures of sporadic medulloblastomas by studying their characteristics in genetically and pathophysiologically relevant mouse models in order to improve treatment options. I hypothesize that each particular medulloblastoma subtype arises from distinct germinal zones of the cerebellum and consequentially have distinctive molecular signatures and dependence on signaling pathways related to their tumor cell of origin. I will use a novel genetic technique to generate mosaic mice where genes are conditionally mutated at endogenous loci and simultaneously marked with GFP in single cells under both temporal and cell type-specific control. This sophisticated approach will allow me to address fundamental questions in medulloblastoma biology such as tumor cell of origin, role of microenvironment in promoting or restricting tumor formation, unambiguously determine the molecular profiles of GFP+ marked tumor ceils during different tumor stages, as well as characterize treatment-resistant GFP+ tumor cells. These studies will be performed under the mentorship of Dr. Alexandra Joyner, an expert in neural development and mouse genetics, and the co-mentorship of Dr. Eric Holland, an expert in brain tumor biology. Both mentors and their laboratories provide the optimal setting for developing expertise in the techniques and methodologies required for future success in this field after my transition to an independent faculty position during the period of this K award. Weill Cornell's outstanding institutional commitment to fostering my career development is shown by limiting clinical responsibilities and administrative duties to allow at least 75% effort devoted to research, and providing independent research space and a tenure-track faculty position at the time of my transition to an independent research scientist. Public Health Relevance: Medulloblastoma is the most common brain tumor in children and one of the leading causes of death in this age group. The goal ofthis application is to better understand the molecular basis of medulloblastoma using genetically relevant mouse models with the aim of identifying new target(s) for therapy for this devastating cancer.